Elucidation of physiological and pathological roles of TDP-43 through autophagic machinery
| Project/Area Number |
18K07364
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Hashimoto Tadafumi 東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | TDP-43 / FUS / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / TDP=43 / 前頭側頭葉型変性症 / 神経変性疾患 / オートファジー |
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| Outline of Final Research Achievements |
Aberrant accumulation of TDP-43 or FUS in the affected motor neurons of patients with amyotrophic lateral sclerosis (ALS) is a pathological feature of ALS, however the molecular mechanisms whereby TDP-43 induced the neurodegeneration remained unclear. Here, we found that ULK1 mRNA was interacted with TDP-43, and knockdown of TDP-43 reduced the level of protein of ULK1. Knockdown of TDP-43 also reduced the level of LC3-II, indicating that TDP-43 has an important role in the regulation of autophagy. Moreover, ULK1 deficient mice exhibited severer motor dysfunction in the AAV9-TDP-43 model. These data suggest that autophagy regulates neurodegeneration induced by TDP-43.
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| Academic Significance and Societal Importance of the Research Achievements |
脊髄前角の運動ニューロンが変性脱落することにより、重篤な筋萎縮を引き起こす神経難病である筋萎縮性側索硬化症において、どのような機序で運動乳論が神経変性を起こすのか不明であった。本研究ではタンパク質の品質管理に重要な機構であるオートファジーが、TDP-43の神経毒性に関与することを明らかにした。この結果はこれまで根本治療薬のなかった筋萎縮性側索硬化症に、新たな治療標的を提供するものである。
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Report
(4 results)
Research Products
(25 results)
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[Journal Article] Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model2020
Author(s)
Abe Y, Ikegawa N, Yoshida K, Muramatsu K, Hattori S, Murakami M, Tanaka T, Goda W, Hashimoto T, Miyakawa T, Iwatsubo T, Hata J, Niikura T, Yasui M, et al.
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Journal Title
Acta Neuropathol. Commun.
Volume: 8
Pages: 67-67
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease.2019
Author(s)
Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T, Mano A, Yamada K, Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T
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Journal Title
Mol. Neurodegener.
Volume: 14
Pages: 15-15
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Roles of collagen XXV and its putative receptors PTP s/d in intramuscular motor innervation and congenital cranial dysinnervation disorder2019
Author(s)
Haruka Munezane, Hiroaki Oizumi, Tomoko Wakabayashi, Shu Nishio, Tomoko Hirasawa, Takashi Sato, Akihiro Harada, Tomoyuki Yoshida, Takahiro Eguchi, Yuji Yamanashi, Tadafumi Hashimoto, Takeshi Iwatsubo
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Journal Title
Cell Reports
Volume: 29
Pages: 4362-4376
DOI
Related Report
Peer Reviewed / Open Access
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